Tait D. Shanafelt, MD, from Stanford University in California presented the results as a late-breaking abstract at the 2018 ASH Annual Meeting.

“The combination of fludarabine, cyclophosphamide, and rituximab is the most active therapy [in this setting], but one with a high [incidence of] side effects that cannot be tolerated by all CLL patients,” Dr. Shanafelt explained. FCR is primarily used in patients younger than 70 years, but “since the median age at diagnosis for this disease is around 65 to 70 years, half of the patients are not even able to tolerate the therapy.”

With this trial, the researchers evaluated “whether we could improve upon the best current treatment for patients with CLL,” he noted. The ECOG-E1912 study enrolled 529 patients ≤70 years who were diagnosed with CLL (without del17p) and had no recorded history of prior therapy. All patients had an ECOG performance status of 0 to 2 and were able to tolerate FCR.

In a 2:1 ratio, patients were randomized to one of either of the following treatments, which were received every 28 days:

Ibrutinib-rituximab: ibrutinib 420 mg daily plus rituximab (50 mg/m2 on day 1 of cycle 2, followed by 325 mg/m2 on day 2 of cycle 2 and 500 mg/m2 on day 1 of cycles 3-7)

FCR: fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2 on days 1-3, and rituximab (50 mg/m2 on day 1 of cycle 1, followed by 325 mg/m2 on day 2 of cycle 1, and 500 mg/m2 on day 1 of cycles 2-6)

The ibrutinib group included 354 patients, while 175 were enrolled in the FCR arm.

Patient characteristics were similar between the two treatment arms. The median age was 57 in the ibrutinib group and 58 in the FCR group (ranges not provided).

After a median follow-up of 33.4 months (range not reported), the researchers recorded a total of 77 PFS events – 37 in the ibrutinib group and 40 in the FCR group. Fourteen patients died – four in the ibrutinib group and 10 in the FCR group.

This translated to a 65-percent reduction in the risk of disease progression or death (primary endpoint) with ibrutinib compared with FCR (hazard ratio [HR] = 0.35; 95% CI 0.22-0.5; p<0.001). There also was an OS advantage with ibrutinib (secondary endpoint; HR=0.17; 95% CI .05-0.54; p<0.003).

The improvement in PFS was seen across subgroups, Dr. Shanafelt noted. For example, for the 329 patients with IGHV mutation status available, 71.1 percent had IGHV-unmutated disease; within this group, ibrutinib lowered the risk of disease progression or death by 74 percent, compared with FCR (HR=0.26; 95% CI 0.14-0.5; p<0.0001). However, the impact of treatment did not differ significantly in the patients with IGHV-mutated disease (HR=0.44; 95% CI 0.14-1.36; p=0.07).

Dr. Shanafelt commented that the ibrutinib-rituximab regimen was “less toxic than our historical therapy,” with more patients in the FCR group experiencing a grade ≥3 treatment-related adverse event (72% vs. 58%; p=0.0042; TABLE).

Together, these results “establish ibrutinib-based therapy as the most effective treatment … for untreated patients,” Dr. Shanafelt concluded. “In cancer trials, [we want] to improve the effectiveness of treatment or reduce its side effects. This trial is one of the rare circumstances where we’ve done both.”

The younger age of this patient group represents a potential limitation of this finding, as these results may not be generalizable to the larger CLL population, which generally consists of patients older than 65 years.

The results of this trial also should be interpreted in light of results from the ALLIANCE trial presented as a plenary abstract at the ASH annual meeting, which showed that ibrutinib alone was superior to chemoimmunotherapy with bendamustine and rituximab in older patients with treatment-naïve CLL. Adding rituximab to ibrutinib did not result in improved outcomes. When asked if rituximab was necessary in this setting, Dr. Shanafelt advised caution about cross-trial comparisons – adding that the ECOG-E1912 trial enrolled a younger population.

Each trial demonstrated ibrutinib’s superiority over standard chemoimmunotherapy, however, and the results represent “a paradigm shift from a 6-month course of intravenous chemotherapy to chronic treatment with a pill,” which raises questions about the pharmaco-economics of long-term targeted therapy.

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